title: Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer.
abstract: Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma. The solvent-based traditional taxanes docetaxel and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel, a water-soluble albumin-bound paclitaxel, may carry superior distribution properties into the tumor microenvironment and has shown efficacy in multiple tumor types. We evaluated nab-paclitaxel effects compared with gemcitabine or docetaxel. For pancreatic ductal adenocarcinoma cells AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1, gemcitabine IC50 ranged from 494nM to 23.9 μM; docetaxel IC50 range was from 5 to 34nM; nab-paclitaxel IC50 range was from 243nM to 4.9 μM. Addition of IC25 dose of docetaxel or nab-paclitaxel decreased gemcitabine IC50. Net tumor growth inhibition after gemcitabine, docetaxel or nab-paclitaxel was 67, 31 and 72%, which corresponded with intratumoral proliferative and apoptotic indices. Tumor stromal density was decreased by nab-paclitaxel and to a lesser extent by docetaxel as measured through reduction in α-smooth muscle actin, S100A4 and collagen 1 expression. Animal survival was prolonged after nab-paclitaxel treatment (41 days, P < 0.002) compared with gemcitabine (32 days, P = 0.005), docetaxel (32 days, P = 0.005) and controls (20 days). Survival in nab-paclitaxel/gemcitabine and docetaxel/gemcitabine sequential treatment groups was not superior to nab-paclitaxel alone. Low-dose combination of gemcitabine with nab-paclitaxel or docetaxel was more effective compared with controls or gemcitabine alone but not superior to regular dose nab-paclitaxel alone. Combination treatment of gemcitabine+nab-paclitaxel or gemcitabine+docetaxel increased gemcitabine concentration in plasma and tumor. The superior antitumor activity of nab-paclitaxel provides a strong rationale for considering nab-paclitaxel as first-line monotherapy in pancreatic ductal adenocarcinoma.
authors.affiliation: Division of Surgical Oncology, Department of Surgery.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Awasthi
authors.forename: Changhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Anna M
authors.initials: AM
authors.lastname: Schwarz
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinz
authors.forename: Changguang
authors.initials: C
authors.lastname: Wang
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
mesh_terms: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D000077143:Docetaxel; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D050777:Stathmin / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D050777:Stathmin; D043823:Taxoids; D014404:Tubulin; D003841:Deoxycytidine; D000077143:Docetaxel; D017239:Paclitaxel; D000093542:Gemcitabine